Atomic-level, large-scale structure prediction of G protein-coupled receptors

说明/项目摘要 G蛋白偶联受体（GPCR）是最大的整合膜蛋白家族， 发生在几乎每一个真核细胞中，以将细胞外信号（配体结合）转化为细胞外信号。 细胞内信号（G蛋白激活）。这种基本的生理作用使它们成为最重要的 重要的药物靶点，约占当今现代药物的一半， 毒品显然，GPCR的3D结构将提供必要的原子级信息， 阐明分子组织和用于药物数据库的有效虚拟筛选。然而，在这方面， 除了最近解决的人β 2-肾上腺素能受体外， 获得其他人类GPCR的实验结构信息。在最近成功的基础上， 提出了一种用于GPCR建模的线程组装精化（TASSER）算法， 该提案旨在开发新的计算方法，以产生实验- 经过验证的原子级气相化学还原模型。重点将放在五个药学上重要的家庭 包括肾上腺素能、趋化因子、多巴胺、组胺和毒蕈碱乙酰胆碱。 该项目的具体目标是：（1）开发新的GPCR-TASSER并确定基准 用于原子水平GPCR蛋白质结构建模的算法。(2)开发和优化 复合原子势和还原GPCR势。(3)GPCR-TASSER算法的推广 公共使用和检查。(4)GPCR-TASSER技术在药学上的应用 GPCR。(5)与实验合作者一起验证和完善GPCR模型。 长期目标是：（a）开发一套自动化和原子化的计算机算法， 水平GPCR结构预测（B），以将该方法扩展到蛋白质组学尺度结构建模 （c）建立一个可供公众查阅的全球化学品还原报告中央储存库 算法和结构数据库，旨在最终缓解迫切需要， 生物学和医学界提供详细的原子GPCR结构。

Description/Project Summary G protein-coupled receptors (GPCRs) are the largest family of integral membrane proteins that occur in nearly every eukaryotic cell to transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). This essential physiological role makes them the most important pharmaceutical targets which comprise approximately half of today's modern medicinal drugs. Clearly, 3D-structures of GPCRs would provide essential atomic-level information for elucidating the molecular organization and for efficient virtual screening of drug databases. However, except for the recently solved human beta2-andrenergic receptor, it has not yet been possible to obtain experimental structural information for other human GPCRs. Building on the recent success of the threading assemble refinement (TASSER) algorithm for reduced-level GPCR modeling, this proposal seeks to develop new computational methodologies for the generation of experiment- validated, atomic-level GPCR models. The focus will be on five pharmaceutically important families including Adrenergic, Chemokine, Dopamine, Histamine, and Muscarinic acetylcholine. Specific aims of the project are: (1) Development and benchmarking of a new GPCR-TASSER algorithm for atomic-level GPCR protein structure modeling. (2) Development and optimization of composite atomic and reduced GPCR potentials. (3) Dissemination of GPCR-TASSER algorithm for public use and examination. (4) Application of GPCR-TASSER to the pharmaceutically important GPCRs. (5) Validation and refinement of the GPCR models with experiment collaborators. The long-term goals are (a) to develop a set of computer algorithms for automated and atomic- level GPCR structure prediction (b) to extend the methodology to proteomic-scale structure modeling for all GPCRs in UniProt database (c) to construct a central repository for publicly-accessible GPCR algorithms and structure databases which are designed to eventually alleviate the urgent need in biology and medical communities for the detailed atomic GPCR structures.